PT2066677E - Pyridooxazepine progesteron receptor modulators - Google Patents

Description

ΕΡ 2 066 677 / ΡΤ

DESCRIPTION " Pyridoxazepine Progesterone Receptor Modulators " The present invention relates to (e) -8-fluorodibenzo [b, f] pyrido [1,2-d] oxazepine-1-amine derivatives which are progesterone receptor modulators, with their application in the field of contraception , hormone replacement therapy (HRT) or gynecological disorders therapy, as well as adjuvant therapy for cancer and other diseases, and processes for the manufacture and use of such compounds.

Intracellular receptors are a class of structurally related proteins involved in the regulation of gene transcription. Steroid receptors are a subset of these receptors, including the progesterone receptor (PR), the androgen receptor (AR), the estrogen receptor (ER), the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) . Regulation of a gene requires an intracellular receptor and a corresponding ligand, which has the ability to selectively bind to the receptor in a manner that affects transcription of the gene.

Progesterone receptor modulators (progestogens and antiprogestagens) are known to play an important role in women's health. The natural ligand for PR is the steroid hormone progesterone, but synthetic compounds have been prepared which may also serve as ligands (see, e.g., Jones et al., U.S. Patent No. 5,688,810).

Progestagens are currently widely used for hormonal contraception and in HRT. Other important clinical applications of progestagens are the treatment of gynecological disorders (eg, endometriosis, dysmenorrhea, dysfunctional uterine bleeding, severe premenstrual syndrome), breast cancer, hot flushes and mood disorders, and luteal support during in vitro fertilization. In addition, progestagens are used in combination with other hormones and / or other therapies including, without limitation, chemotherapeutic agents such as cytotoxic and cytostatic agents, immunological modifiers such as interferons and interleukins, hormones of growth and other cytokines, hormonal therapies, surgery and radiation therapy.

It has been shown that the current steroid progestagens are very safe and are well tolerated. Sometimes, however, side effects (eg, breast tenderness, headaches, depression and weight gain) have been reported attributed to these steroid progestagens, either alone or in combination with estrogenic compounds. In addition, steroid ligands for a receptor often show cross-reactivity with other steroid receptors. Many steroid progestagens also bind to, for example, one of androgen, while many antiprogestagens have an affinity for the glucocorticoid receptor.

Non-steroid progestagens have no structural similarity to steroids and may therefore be expected to exhibit different behavior with respect to physico-chemical, pharmacokinetic (PK), or tissue distribution (eg, central nervous system relative to the peripheral), and, more importantly, may show no cross-reactivity or less cross-reactivity to other steroid receptors. Therefore, non-steroid progestagens can be expected to make a difference in these respects and therefore offer advantages over steroid progestagens when applied in therapy.

A group of non-steroidal molecules containing a 1,3,4,14b-tetrahydro-2 H -dibenzo [b, f] -pyrido [1,2-d] oxazepine system has been described as a nucleus as non-steroidal modulators of progesterone receptor with an affinity for the progesterone receptor (WO 03/084963). The disclosed compounds show moderate to strong agonist activity in vitro towards the progesterone receptor. More active compounds show an affinity of 10 nM or less. In addition, some of the compounds of WO 03/084963 showed weak to moderate in vitro anti-progestagen activity. 3 ΕΡ 2 066 677 / ΡΤ

The compounds of the present invention show an agonistic activity similar in vitro to that of the compounds of WO 03/084963. Surprisingly, however, the particular combination of specific substituents, more specifically a 7-position nitrile substituent in combination with a fluoro substituent at the 8-position, gives rise to a greatly increased in vivo progestagenic activity, as indicated by the results of inhibition assays of ovulation. This provides the compounds of the present invention an advantage over known compounds having a similar structure: as recognized by those skilled in the art, high in vivo activity in a test assay is highly indicative of a strong activity in a therapy application, especially in human subjects. In addition, those skilled in the art will recognize that when the in vivo assay uses oral administration, a high activity (i.e., an activity that can be achieved by administering relatively small amounts of compound) is a desirable property for the compounds which therapy can, for example, be administered orally.

Thus, the present invention provides compounds which exert a strong progestogenic effect in vivo. More particularly, the present invention relates to (e) -8-fluorodibenzo [b, f] pyrido [1,2-d] oxazepine-1-amine compounds and to compositions which are high affinity agonists by progesterone , which also show extraordinarily high progestagen potency in vivo.

According to the present invention there are provided the (E) -8-fluorodibenzo [b, f] pyrido [1,2-d] oxazepine-1-amine compounds having the general Formula I: R3

O

Wherein R 1 is (C 1 -C 4) -alkyl, optionally substituted with one or more halogen atoms; and R2 is selected from the group consisting of H, halogen, (C1-C6) alkyl, and CN; and R 3, R 4 and R 5 are each independently H or F.

In one specific embodiment R 1 is CF 3. In another embodiment, R 1 is CH 3.

In one embodiment, R2 is H. In another embodiment, R2 is Cl and in yet another embodiment R2 is CN.

In one embodiment, R 3 is H, In another embodiment, R 3 is F.

In one embodiment, R 4 is H. In another embodiment, R 4 is F.

In one embodiment, R 5 is H. In another embodiment, R 5 is F.

In one embodiment, R 3, R 4 and R 5 are H. In another embodiment, R 3 is F and both R 4 and R 5 are H. In another embodiment, R 4 is F and both R 3 and R 5 are H and in yet another embodiment, R 5 is F and both R 3 and R 4 are H.

In one specific embodiment, R 1 is CF 3, R 2 is H, R 3 is H, R 4 is H and R 5 is H.

In another specific embodiment, R 1 is CF 3, R 2 is Cl, R 3 is H, R 4 is H and R 5 is H.

In addition, the present invention provides compounds useful as intermediates or precursors in the preparation of compounds of Formula I wherein R 1, R 3, R 4 and R 5 have the meaning given above and wherein R 2 is H. These (e) -8-fluorodibenzo [b , f] pyrido [1,2-d] oxazepine-1-amine have a general Formula II where R 1 is (C 1 -C 4) alkyl optionally substituted with one or more halogen atoms. 5 ΕΡ 2 066 677 / ΡΤ 5 ΕΡ 2 066 677 / ΡΤ

Formula II

It will be appreciated that in both Formula I and Formula II the amino substituent at the 1-position and the hydrogen-bond substituent at the 14b-position are located on the same side of the ring system. This relative stereochemistry, which is stereochemistry where the absolute orientation of one substituent is related to the absolute orientation of another substituent, is reflected in the nomenclature of the compounds through the use of the prefix (cis) -.

The compounds of the invention are intended for use in therapy. The invention provides a contraceptive composition comprising a compound of the invention and a contraceptively acceptable carrier. The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutical composition for hormone replacement therapy is envisaged. In another embodiment, a pharmaceutical composition for the treatment of a gynecological disorder is envisaged.

In addition, the invention involves a use of a compound of the invention for the manufacture of a contraceptive. The invention also provides the use of a compound of the invention for the manufacture of a medicament. In one embodiment, the use of a compound of the invention is for the manufacture of a medicament for hormone replacement therapy, or, in another embodiment, for the treatment of a gynecological disorder.

In addition, the invention provides a method of contraception comprising administering a contraceptively effective amount of a compound of the invention to a subject in need thereof.

In addition, the invention provides a compound of Formula II useful in the manufacture of a compound of Formula I, since the compounds of Formula II serve as intermediates in the preparation of compounds of Formula I. As shown in Scheme 1, such intermediates of Formula II in compounds of Formula I through the use of CuCN, optionally in the presence of Cul.

Scheme 1

Compounds of Formula II may be prepared as described in WO 03/084963. Optionally, various compounds of Formula I may be prepared in which R2 has the meaning given above except that R2 is not hydrogen, from compounds of Formula II. The latter compounds can be chlorinated using N-chlorosuccinimide or other chlorination reagents known in the art, to yield compounds of Formula I in which R 2 = Cl. These chlorinated compounds can be converted into compounds of Formula I in which R2 = (other) halogen, (C1-C6) alkyl or CN using various reactions known in the art (Scheme 2).

Scheme 2

The racemates of the compounds of Formula I or Formula II may be separated into their enantiomers using various methods known in the art, one such method being the use of chiral column chromatography. 7 ΕΡ 2 066 677 / ΡΤ

Another suitable method of resolution is the use of optically pure acids such as tartaric acid or pheninds to prepare salts of diastereomerically pure amines of Formula III in which R2 has the meaning as in Formula I. The methods for preparing the amines of Formula III and the use of these amines to prepare the amides of Formula II in WO 03/084963.

Formula III

The terms used in this description have the following meaning:

(C1-C4) alkyl is a branched or unbranched alkyl group having 1, 2, 3 or 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like;

(C 1 -C 6) alkyl is a branched or unbranched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl , pentyl, sec-pentyl, isopentyl, hexyl, sec-hexyl, isohexyl and the like;

Halogen refers to fluorine, chlorine, bromine or iodine;

For the purposes of the present invention, and in accordance with the practices of the Chemical Abstracts Service (see Naming and Indexing of Chemical Substances for CHEMICAL ABSTRACTS, American Chemical Society, Columbus, Ohio, 1987) to fused polycyclic compounds such as those of the present invention is to be understood as meaning the relative stereochemistry wherein the ring substituent at the 1-position (Formula I) is located on the same side of said ring as the bridging substituent Formula I is hydrogen) at the 14b-position. The meaning of the term (cis) will be further clarified for those skilled in the art from the illustrations in the various Figures, Diagrams and Reaction Schemes. 8

ΕΡ 2 066 6 77 / EN

A racemate is a mixture in equal parts of enantiomers; as will be known to those skilled in the art, a racemate, also called a racemic mixture or racemic preparation, is optically inactive since the optical activities of the dextrorotatory and levorotatory enantiomers cancel. See also R.T. Morrison and R. N. Boyd, Organic Chemistry (3rd Edition), Allyn & Bacon, Boston, 1973, pp. 127.

A levorotatory enantiomer is called when it is discovered, in determining its optical activity, that it produces an anti-clockwise rotation of the plane of polarized light. Likewise, a dextrorotatory enantiomer is called if said rotation of the plane of polarized light occurs clockwise. (see also R. T. Morrison and R. N. Boyd, Organic Chemistry (3rd Edition), Allyn & Bacon, Boston, 1973, pp. 119). As will be well known to those skilled in the art, however, the signal (" + " or " more " for dextrorphic and or " less " for left-handed) rotation of the plane of polarized light depends on the temperature, (when determining the rotation of a compound in solution) of the concentration and solvent (see also J. March, Advanced Organic Chemistry, 2nd Edition, McGraw-Hill Kogakusha, Tokyo 1977, pp. 87 and following). The affinity and efficacy by the progestagen receptor of the compounds according to the invention makes them suitable for use in fertility and reproduction control, for example, female contraception, and also for female HRT, for the treatment of gynecological disorders, as components of male contraception and in diagnostic methods focused on the amount and / or location of progesterone receptors in various tissues. For the latter purpose it may be preferred to make isotopically-labeled variants of the compounds according to the invention.

The compounds of the invention may be useful for the treatment of endometriosis, menorrhagia, menometrorrhagia, dysmenorrhea, acne, fibroids, osteoporosis as well as other bone disorders, repair of bone fractures, sarcopenia, fragility, aging of the skin, female sexual dysfunction, symptoms post-menopausal, atherosclerosis, aplastic anemia, lipodystrophy, side effects of chemotherapy, tumors (eg chest, ovary and uterus) and others.

Suitable routes of administration for the compounds of the invention (also called the active ingredient) are oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) or administration by means of an implant. In a specific embodiment, the compounds may be administered orally. The exact dose and administration regime of the active ingredient, or a contraceptive or a pharmaceutical composition thereof, will necessarily be dependent on the therapeutic effect to be achieved (e.g., contraception, HRT) and may vary with the particular compound, the route of administration, and the age and condition of the individual subject to whom the drug is being administered. The dosage for humans is likely to contain from 0.0001 to 25 mg per kg of body weight. The desired dose may be presented as a dose or as multiple sub-doses given at appropriate intervals.

Accordingly, the present invention also relates to contraceptive and pharmaceutical compositions comprising a compound according to Formula I in admixture with pharmaceutically acceptable auxiliaries, and optionally with other therapeutic agents. Auxiliaries must be " acceptable " in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient.

The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration by means of an implant. The compositions may be prepared by any method well known in the art of pharmacy, for example, using the methods as described in Gennaro et al., Remington's Pharmaceutical Sciences (18th edition, Mack Publishing Company, 10, 466, 677, 1990 , see especially Part 8: Pharmaceutical

Preparations and Their Manufacture).

Such methods include the step of bringing together the active ingredient with any auxiliary agent. The auxiliary agent (s), also called accessory ingredient (s), includes those conventionally in the art (Gennaro, supra), such as carriers, inerts, binders, diluents, disintegrants , lubricants, colorants, flavoring agents, antioxidants, and wetting agents.

Contraceptive and pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a cake or a paste. The compositions may furthermore be processed into a suppository or an enema for rectal administration. The invention further includes a contraceptive composition and a pharmaceutical composition as described herein in combination with the packaging material, including instructions for use of the composition for use as described herein.

For parenteral administration, appropriate compositions include a sterile aqueous or non-aqueous injection. The compositions may be presented in single or multi-dose containers, for example in small vials and sealed ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier , for example water, before use. For transdermal administration, for example gels, adhesives or sprays may be considered. Compositions or formulations suitable for pulmonary administration, for example by nasal inhalation, include fine dust or mists which may be generated by pressurized dosing aerosols, nebulizers or insufflators.

The compounds of the invention may also be administered in the form of devices consisting of a core of active material coated with a release membrane at a regulated rate. Such implants are intended to be applied subcutaneously or locally, and will release the active ingredient at an approximately constant rate over relatively large periods of time, for example from weeks to years. Methods for the preparation of pharmaceutical implant devices such as these are known in the art, for example as described in EP 303306.

The compounds of the invention may also be administered in the form of a vaginal ring as described for example in EP 876815.

The compounds of the invention may be administered in conjunction with estrogens, androgens, progestagens, antiprogestagens, and other suitable compounds such as folic acid, vitamins, minerals, and the like.

EXAMPLES

The invention is further described in the following examples.

The following abbreviations are used in the examples: CH 2 Cl 2: dichloromethane CuBr: copper (I) bromide

CuCN: copper (I) cyanide

Cul: copper (I) iodide DMSO: dimethylsulfoxide DPPA: diphenylphosphoryl azide e.e .: enantiomeric excess K2 CO3: potassium carbonate M: molar

MgSO4: magnesium sulfate

NaHCO 3: sodium hydrogen carbonate

NaOH: sodium hydroxide

Na2 SO4: Sodium sulfate NCS: N-chlorosuccinimide NH4 OH: ammonium hydroxide NMP: N-methylpyrrolidone NMR: Nuclear Magnetic Resonance 12 ΕΡ 2 066 677 / ΡΤ

Filter P.S .: Phase Separation Filter S1O2: silicon dioxide (silica gel) THF: tetrahydrofuran

Example 1

Preparation of (-) - (cis) -N- (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula II, R1 = CF3, R2 = R3 = R4 = R5 = H) a. 2 - [[(5-bromo-2,4-difluorophenyl) imino] methyl] phenol

A solution of 2,4-difluoro-6-bromoaniline (5 g, 24 mmol), salicylic aldehyde (2.5 mL, 24 mmol) and p-toluenesulfonic acid (14 mg, 0.07 mmol) in toluene (120 mL) was refluxed in a Dean-Stark device for 2.5 hours and then allowed to cool to room temperature. After triethylamine (1 mL) was added, the reaction was concentrated to give the crude title compound (7.3 g, 97%) which was used without further purification. NMR (400 MHz, CDCl3) 6.95-6.99 (m, 1H), 7.01-7.06 (m, 2H), 7.39-7.45 (m, 2H), 7.48 -7.52 (m, 1H), 8.66 (s, 1H), 12.69 (s, 1H). (m / z) = 312 + 314 (M + H) +. B. To a solution of 2 - [[(5-bromo-2,4-difluorophenyl) imino] methyl] phenol (14.4 g, 5 g, 46.5 mmol) in DMSO (0.43 L) was added K 2 CO 3 (12.8 g, 71.8 mmol) and 18-Crown-6 (145 mg, 0.55 mmol). The resulting mixture was stirred at 140 ° C for 2.5 h and then allowed to cool to ambient temperature. Water (0.6 L) was added and the product collected by filtration, washed with water and dried under reduced pressure to give the title compound (15.7 g, 100%), which was used without further purification. 1H NMR (400 MHz, CDCl3) 6.93-6.96 (d, J = 8.2, 1H), 7.10-7.14 (d, J = 8.2, 1H), 7.23 (M, 1H), 7.46-7.51 (m, 1H), 7.55-7.57 (d, J = 7, 8, 1H), 8.47 (s, 1H). (m / z) = 292 + 294 (M + H) +. 13 ΕΡ 2 066 677 / ΡΤ c. (±) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxaxepine-1-carboxylic acid

To a stirred solution of 8-bromo-7-fluoro-dibenzo [b, f] [1,4] oxazepine (46.5 mmol) in xylene (26 g) was added glutaric anhydride (7.2 g, 63 mmol) mL) and the mixture was heated to 140 ° C for 120 h. The reaction mixture was allowed to cool to room temperature, ether was added and the solution (3 times) was extracted with 2M NaOH. The pH of the combined extracts was adjusted to pH 4 by the addition of 3M hydrochloric acid. The product was collected by filtration and dried to give the title compound (14.1 g, 81%) which was used without further purification. NMR (400 MHz, CDCl3) 2.03-2.14 (m, 1H), 2.31-2.4 (m, 1H), 2.53-2.62 (m, 1H), 2.67 (M, 1H), 3.55-3.60 (m, 1H), 5.46-5.49 (m, 1H), 7.05-7.99 (d, J = 8, 6, 1H), 7.11-7.32 (m, 4H), 7.56-7.59 (d, J = 7.8, 1H). (m / z) = 406 + 408 (M + H) +. d. (±) - (cis) - (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d] To a solution of methyl (±) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo- 2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-carboxylic acid (13.1 g, 32.3 mmol) in toluene (660 mL) was added triethylamine ( 7.6 mL, 54 mmol) and biphenyl phosphorazidate (9.1 mL, 42 mmol). The reaction mixture was refluxed for 2 h. Subsequently, methanol (31.9 mL, 787 mmol) was added and stirred continuously for 2 h at 70 ° C. After cooling to room temperature, the reaction mixture was dried over a PS filter and evaporated to give the crude title compound (30.5 g, 100%), which was used without further purification, (m / z) = 435 + 437 (M + H) +. and . (±) - (cis) - (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-yl) carbamate

A borane-tetrahydrofuran complex (1.0 M in THF, 970 mL, 970 mmol) was added dropwise to a stirred solution of (Â ±) - (cis) - (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-yl) -carbamate (105.2 g, 242 mmol) in THF (1 L). The resulting mixture was stirred at room temperature for 3 h. Subsequently, hydrochloric acid (1 M) was added dropwise until the gas formation stopped (+ 550 mL). The resulting mixture was stirred for 1 h and then diluted with ethyl acetate; the organic layer was washed with water and brine. After drying (MgSO4) the solvent was evaporated under reduced pressure to give the crude title compound (98.5 g, 97%). (m / z) = 421 + 423 (M + H) +. (Â ±) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepine -blade

A mixture of acetic acid (40 mL) and hydrobromic acid (48%, 20 mL) was added to (±) - (cis) - (7-bromo-8-fluoro-1,3,4,14b- dihydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (20.2 g, 48 mmol) was added and stirred overnight at 100 ° C. After cooling, the reaction mixture was poured into ice cold 1M NaOH solution. The organic layer was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the crude title compound (15.9 g, 91%) which was used without further purification. (m / z) = 363 + 365 (M + H) +. g. (-) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] To a solution of (±) - (cis) -2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane 2-oxazepine-1-amine -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-amine (18, 58 g, 51.18 mmol) in 300 mL of CH 2 Cl 2 and 60 mL of 2-propanol at 50 ° C was added a hot solution of (+) - phenols (6.19 g, 25.59 mmol) in CH 2 Cl 2 (300 mL) and 2-propanol (75 mL). The mixture was heated to 86 ° C. About 500 mL of CH2 Cl2 was removed by careful evaporation, and 310 mL of 2-propanol was added; the mixture was then further concentrated to a final weight of about 250 g, and then gradually cooled to 35 ° C. After 1 h, the crystals formed were collected by filtration, washed with 2-propanol and dried to give 12.7 g of crude product (e.e. = 95%). This compound was further recrystallized from methanol: CH 2 Cl 2: 2-propanol (7: 5: 2) to give the title compound (12.3 g, 39%, e.e. = 99.8%). H. (-) - (eis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin- blade

To a solution of (-) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2 H -dibenzo [b (4 S) -2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-trifluoro [1,2- d] [1,4] oxazepin-1-amine dioxaphosphorinane (1: 1) (45.42 g, 75 mmol) in 1 L of ethanol: CH 2 Cl 2 (1: 9), and the resulting biphasic mixture was vigorously stirred at room temperature for 0.5 h. The aqueous layer was extracted with CH 2 Cl 2 (400 mL) and the combined organic layers were washed with 0.4 M NaOH, dried (Na 2 SO 4) and evaporated under reduced pressure to give the title compound (27.2 g, g, 100%). 1 H NMR (400 MHz, CDCl 3) 1.40-1.51 (m, 1H), 1.69-1.89 (m, 2H), 2.14-2.22 (m, 1H) 11-3.29 (m, 1H), 3.38-3.45 (m, 1H), 3.68-3.76 (m, 2H), 6.87-6.90 (d, J = 8). , 7.01 (s, 1H), 7.03-7.30 (m, 5H). 19 F NMR (400 MHz, CDCl 3) -118.27. (m / z) = 363 + 365 (M + H) +. (e.e. = 99.9%) (chiralpak AD-H 25 * 0.46 cm, heptane: ethanol = 8: 2). (m / z) = 363 + 365 (M + H) +.

[Î ±] D20.5 = -202Â ° (c = 1.0, CHCl3) i. (-) - (cis) -N- (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 4-oxazepin-1-yl) -2,2,2-trifluoroacetamide To a solution of (-) - (cis) -7-bromo-8-fluoro-1,3,4,14b-tetrahydro- 2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-amine (27.51 g, 75.78 mmol) in a mixture of CH2 Cl2 (866 mL) 56 mL) was added trifluoroacetic anhydride (33.84 mL, 242 mmol) and the resulting mixture was stirred at room temperature for 1.5 h. The crystals formed were collected by filtration, washed with CH2 Cl2 and water, and dried under reduced pressure to give the title compound (-) - (cis) -N- (7-bromo-8- fluoro-1,3,4,14b-tetrahydro-2 H -dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -16E02,666,677 / ΡΤ2 , 2,2-trifluoroacetamide (31.36 g, 90%). 1 H NMR (400 MHz, DMSO) 1.60-1.85 (m, 3H), 1.97-2.04 (m, 1H), 3.07-3.16 (m, 1H) 73-80 (d, J = 12.9, 1H), 4.07-4.10 (d, J = 9.7, 1H), 4.31-4.42 (m, 1H), 7 (M, 2H), 7.24-7.33 (m, 3H), 9.18-9.21 (d, J = 9.7, 1H). (m / z) = 459 + 461 (M + H) +.

[α] D20 = -197 ° (c = 1.0055, THF).

Example 2

Preparation of (-) - (cis) -N- (7-cyano-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, pyrido [1,2- d] 4-oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = R3 = R4 = R5 = H)

A mixture of (-) - (cis) -N- (7-bromo-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- (17 g, 37 mmol), CuCN (8.19 g, 91.5 mmol), CuI (0.754 g, 3 mmol) 9 mmol) and NMP (178 mL) for 20 minutes at 180 ° C, 300 Watt with microwave cooling (5 portions). After cooling, the reaction mixture was poured into water, diluted with NH4 OH solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2 SO4) and concentrated under reduced pressure. The remaining white solid was washed with diethyl ether and crystallized to give the title compound (8.1 g, 54%). NMR (400 MHz, DMSO) 1.66 (m, 1H), 1.74 (m, 1H), 1.82 (m, 1H), 2.01 (m, 1H), 3.16 (D, J = 10.01, 1H), 4.39 (m, 1H), 7.10 (doublet, J = 7.74, 7.3 and 1.32 Hz, 1H), 7.20 (doublet, J = 7.74 and 1.70 Hz, 1H), 7.23 (doublet, J = 7.93 and 1.32 Hz 1H), 7.42 (d, J = 9.44, 1H), 7.57 (d, J = 9.44, J = 6.42, 1H), 9.21 (d, J = 10.01, 1H). 19 F NMR (400 MHz, DMSO) -119.08 (Ar-F), -74.96 (COCF 3). and is. = 100%, (chiralpak AD-H 25 * 0.46 cm, heptane: isopropanol = 9: 1). (m / z) = 405 (M + H) +.

[a] d 20.5-214 ° (c = 1.03, THF). 17 ΕΡ 2 066 677 / ΡΤ

Example 3

Preparation of (-) - (cis) -N- [7-cyano-6-chloro-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl] -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = Cl, R3 = R4 = R5 = H) To a suspension of (-) - N- [7-cyano-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl ] -2,2,2-trifluoroacetamide (17.1 g, 42.2 mmol) in THF was added NCS (6.16 g, 46.4 mmol) and hydrochloric acid (7.8 mL, 46.4 mmol and the resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was then poured into water and extracted with ethyl acetate (2 times). The combined organic layers were washed with saturated aqueous NaHCO 3 and brine, dried (Na 2 SO 4) and evaporated to give the crude which was purified by flash chromatography (SiO 2, ethyl acetate / heptane) (-) - (cis) -N- (7-cyano-6-chloro-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (16.1 g, 78%). 1H NMR (400 MHz, CDCl3) 1.64 (m, 1H), 1.91 (m, 1H), 1.94 (m, 1H), 2.02 (m, 1H), 2.88 (m (D, J = 1.55 Hz, 1H), 4.91 (m, 1H), 6.97 (d, J = 9.44 Hz, 1H), 7.19-7.40 (m, 4H), 7.66-7.74 (d, J = 8.2 Hz, 1H). 19 F NMR (400 MHz, CDCl 3) -105.82 (Ar-F), -76.33 (COCF 3). and is. = 100% (chiralpak AD-H 25 * 0.46 cm, heptane: isopropanol = 9: 1) (m / z) = 440 (M + H) +.

[Î ±] D20.5 = -197Â ° (c = 1.11, THF).

Example 4

Preparation of (-) - (cis) -N- (6,7-dicyano-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl) -2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = CN, R3 = R4 = R5 = H)

A mixture of (-) - (cis) -N- (7-cyano-6-chloro-8-fluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (7.66 g, 17.4 mmol), CuCN (3.9 g, 43.5 mmol ), CuBr (2.5 g, 17.4 mmol) and NMP (105 18 Ρ Ρ 2 066 677 / ΡΤ ml) for 20 minutes at 180 ° C, 300 Watt with microwave cooling (3 portions). After cooling to room temperature, the reaction mixture was poured into water (1 L), stirred for 10 minutes, and the precipitate was isolated. The precipitate was redissolved in ethyl acetate and the solids removed by filtration. The clear solution of ethyl acetate was washed with brine, dried (Na2 SO4) and evaporated to dryness to give the crude compound which was purified by flash chromatography (SiO2, heptane: ethyl acetate : CH 2 Cl 2 = 7: 2: 1) and crystallized to give the title compound (4.09 g, 54%). NMR (400 MHz, DMSO) 1.68 (m, 1H), 1.82 (m, 1H), 1.84 (m, 1H), 2.04 (m, 1H), 3.47 (m, 1H), 3.87 (m, 1H), 4.37 (d, J = 9.44 Hz, 1H), 4.45 (m, 1H), 7.18-7.38 (m, 4H), 7.88 (d, J = 9.44 Hz, 1H), 9.25 (d, J = 8.6 Hz, 1H). 19 F NMR (400 MHz, DMSO) -113.21 (Ar-F), -74.82 (COCF 3). and is. = 99.9% (chiralpak AS-H 25 * 0.46 cm, heptane: isopropanol = 8: 2) (m / z) = 431 (M + H) +.

[a] d 20.5 = -267 ° (c = 1.11, THF).

Example 5

Preparation of (-) - (eis) -N- (7-cyano-6-chloro-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1 , 2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = Cl, R3 = R5 = H, R4 = F) a. To a solution of 4-bromo-3-fluorophenol (89 g, 465.9 mmol) in a mixture of CH 2 Cl 2 (940 mL) and H 2 SO 4 (52.1 mL, 978 mmol) at 0 ° C was added HNO3 (65%) (32.9ml, 468mmol) dropwise (the mixture changed from colorless to black). The resulting mixture was stirred at 0 ° C then poured into water. The organic layer was washed with brine, dried (Na 2 SO 4), and the solvent was evaporated under reduced pressure to give the crude product which was purified by flash chromatography (SiO 2, heptane: toluene = 1: 3) to give 4-bromo-5-fluoro-2-nitrophenol (49.5 g, 45%). 1 H NMR (400 MHz, CDCl 3) 6.95 (d, J = 9.0, 1H), 8.38 (d, J = 6.2, 1H), 10.69 (s, 1H). 19 ΕΡ 2 066 677 / ΡΤ b. 2-amino-4-bromo-5-fluorophenol

A suspension of Na2S204 (51.6 g, 296 mmol) in water (122 mL) was slowly added to a refluxing mixture of 4-bromo-5-fluoro-2-nitrophenol (14 g, 59.3 mmol) in ethanol (1000 mL). The resulting mixture was refluxed for 1 h. After cooling the salts were filtered and the filtrate was partially concentrated. Salt was added, extracted with diethyl ether, the extract dried, and concentrated to give the crude title compound which was used without further purification (9.2 g, 75%). NMR (400 MHz, DMSO) 4.65 (broad, 2H), 6.60 (d, J = 11.3, 1H), 6.76 (d, J = 7.8, 1H), 9.80 (br, 1H). W. 4-bromo-2 - [[(2,4-difluorophenyl) methylene] amino] -5-fluorophenol

A solution of 2-amino-4-bromo-5-fluorophenol (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and p-toluenesulfonic acid ( 100 mg, 0.52 mmol) in toluene (250 mL) in a Dean-Stark device for 0.5 hours and then allowed to cool to ambient temperature. After triethylamine (1 mL) was added, the reaction was concentrated under reduced pressure to give the crude compound, which was used without further purification (16.1 g, 99%). NMR (400 MHz, CDCl3) 6.83 (d, J = 10.2, 1H), 6.93 (m, 1H), 7.01 (m, 1H), 7.49 (d, J = 7.6, 1H), 8.13 (m, 1H), 8.85 (s, 1H). d. To a solution of 4-bromo-2 - [(2,4-difluorobenzylidene) amino] -5-fluorophenol (15) g, 45.4 mmole) in 60 mL of DMF was added CS 2 CO 3 (22 g, 67.5 mmole). The resulting mixture was stirred at 50 ° C for 3 h and allowed to cool to ambient temperature. Water was added and the product collected by filtration, washed with water, and dried under reduced pressure to give the title compound which was used without further purification (14.1 g, 100%). . NMR (400 MHz, CDCl3) 6.82-6.99 (m, 3H), 7.33 (m, 1H), 7.55 (d, J = 7.8, 1H), 8.38 s, 1H). 20 ΕΡ 2 066 677 / ΡΤ e. (±) - (cis) -7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepine-1-carboxylic acid

To a stirred solution of 8-bromo-3,7-difluoro-dibenzo [b, f] [1,4] oxazepine (14.4 g, 46%) was added glutaric anhydride (7.93 g, 69.5 mmole) 4 mmol) in xylene (30 mL) and the mixture was heated to 150 ° C for 72 h. The reaction mixture was allowed to cool to room temperature, and diethyl ether was added. The product was collected by filtration and dried to give the title compound which was used without further purification (16.2 g, 82%). f. (±) - (cis) - (7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl) carbamate To a solution of (±) - (cis) -7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro- 4-oxo-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-carboxylic acid (16.2 g, 38.2 mmol) in toluene (500 mL) triethylamine (9.7 mL, 68 mmol) and DPPA (10.6 mL, 49.1 mmol). The reaction mixture was refluxed for 2 hours. Subsequently, methanol (40 mL) was added and stirring was continued overnight at 70 ° C. After cooling, the reaction mixture was washed with 0.5 M NaOH solution (3 times), dried (Na 2 SO 4) and evaporated to give the title compound which was used without further purification (17: 3 g, 100%). (m / z) = 453 + 455 (M + H) +. g. (±) - (cis) - (7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 4] oxazepin-1-yl) carbamate

Borane (1.0 M in THF, 38.3 mL, 38.3 mmol) was added dropwise to a stirred solution of (Â ±) - (cis) - (7-bromo-8,12-dif methyl-4-oxo-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate ( 38.2 mmol) in THF (200 mL). The reaction mixture was stirred at 30 ° C for 1 h. Subsequently, water was added dropwise until the gas evolution was complete. The resulting mixture was stirred for 1 h and then diluted with ethyl acetate (300 mL) and washed with brine. After drying (Na 2 SO 4) the solvent was evaporated under reduced pressure to give the crude title compound (16.7 g, 100%). (m / z) = 439 + 441 (M + H) +. (±) - (eis) 7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-amine

A mixture of acetic acid (80 mL) and hydrobromic acid (48%, 40 mL) was added to (±) - (eis) - (7-bromo-8,12-difluoro-1,3,4,14b tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (38.2 mmol) was added and the mixture was stirred for overnight at 100 ° C. After cooling the reaction mixture was poured into ice cold 1N NaOH solution (pH 9). The organic layer was washed with brine, dried (Na2 SO4), and the solvent was evaporated under reduced pressure to give the crude title compound (12.7 g, 87%). , which was used without further purification. (m / z) = 381 + 33 (M + H) +. (-) - (cis) -7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepin-1-amine (4S) -2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide (1: 1) To a solution of (±) ) -7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin- amine (12.06 g, 31.65 mmol) in 120 mL of CH2 Cl2, 25 mL of 2-propanol and 25 mL of ethanol at 40 ° C was added a hot solution of (+) - phenols (3.84 g, 15.82 mmol) in 50 mL of CH2 Cl2, 25 mL of 2-propanol and 25 mL of ethanol.

The mixture was warmed to 40øC, CH 2 Cl 2 was carefully evaporated to a small amount of crystals, and the mixture was then gradually cooled to room temperature. The precipitate was filtered and recrystallized to give the title compound (3.94 g, 20%). j. (-) - (eis) -7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepine-1-amine To a solution of the phenthosphonic salt obtained in the previous step (3.94 g, 6.32 mmol) in 150 mL ethanol: CH 2 Cl 2 (1: 9), 1 N NaOH (45 mL, 45 mmol) and the resulting mixture was stirred at room temperature for 1 h. The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers were washed with 0.5 N NaOH, dried (Na 2 SO 4) and evaporated under reduced pressure to give the crude title compound (2.32 g, 96%). and is. = 98.9% (chiralpak AD-H 25 * 0.46 cm, heptane: 2-propanol = 9: 1). k. (-) - (cis) -N- (7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide To a solution of (-) - (cis) -7-bromo-8,12-difluoro-1,3,4,14b- tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-amine (2.32 g, 6.09 mmol) in a mixture of methanol (80 mL) and triethylamine (5.1 mL, 36.3 mmol) was added ethyl trifluoroacetate (4.3 mL, 36.3 mmol) and the resulting mixture was stirred at room temperature for 2 h. Water (120 mL) was added and stirred for another 10 minutes. The precipitate formed was filtered to give the title compound (2.74 g, 94%). 1. (-) - (cis) -N- (7-cyano-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] ] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

A mixture of 2.74 g (5.74 mmol) of (-) - (cis) -N- (7-bromo-8,12-difluoro-1,3,4,14b-tetrahydro- 2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide, CuCN (1.3 g, 14.3 mmol), Cul (0.123 g, 0.57 mmol) and NMP (25 mL) in a microwave for 20 minutes at 180 ° C, 300 Watt with cooling. After cooling, the reaction mixture was poured into water (500 mL). The precipitate, containing the product and the salts, was redissolved in ethyl acetate and the salts filtered. The organic layer was washed with NH4 OH solution, water, and brine, dried, and concentrated to give the crude product which crystallized to give the title compound (1.45 g, 59%). . NMR (400 MHz, DMSO) 1.60-1.86 (m, 3H), 2.01 (m, 1H), 3.15 (m, 1H), 3.86 (m, 1H), 4.133 (m, d, J = 10.0, 1H), 4.35 (m, 1H), 7.00 (m, 1H), 7.03 (m, 1H), 7.44 (d, J = 1H), 7.6 (d, J = 6.3, 1H), 9.23 (broad d, J = 7.8, 1H). (m / z) = 424 (M + H) +. 23 ΕΡ 2 066 677 / ΡΤ m. (-) - (cis) -α- (7-cyano-6-chloro-8,12-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- -d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

Preparation analogous to Example 3 was prepared from (-) - (cis) -N- (7-cyano-8,12-difluoro-1,3,4,14b-tetrahydro-2H- dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide to give the crude product which was purified by flash chromatography (SiO2 , CH 2 Cl 2 / toluene = 1: 9) and crystallized to give (-) - (cis) -N- (7-cyano-6-chloro-8,12-difluoro-1,3,4,14b-tetrahydro -2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (0.719 g, 46%).

Melting temperature 174-175 ° C. NMR (400 MHz, CDCl3), 1.65 (m, 1H), 1.90 (m, 2H), 2.02 (m, 1H), 2.89 (m, 1H), 3.04 (m, m, 1H), 2.39 (m, 1H), 4.86 (m, 1H), 6.95 (m, 3H), 7.29 (m, 1H), 7.66 (broad, 1H). and is. = 100%, Rf = 25.0 minutes (chiralpak OJ-H 25 * 0.46 cm, heptane: ethanol = 9: 1). (MIM) = 457.

[α] D20 = -192 ° (c = 0.885, THF).

Example 6

Preparation of (-) - (cis) -N- (7-cyano-6-chloro-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1 , 2-d] [1,4] oxazepin-1-yl) acetamide (Formula I, R1 = CH3, R2 = Cl, R3 = R4 = H, R5 = F) a. 4-bromo-2 - [[(2,6-difluorophenyl) methylene [amino] -5-fluorophenol

A preparation analogous to Example 5, step c, was prepared from 2-amino-4-bromo-5-fluorophenol (11 g, 53.4 mmol) and 2,6-difluorobenzaldehyde (5.8 mL, 53.4 mmol) gave 4-bromo-2 - [[(2,6-difluorobenzylidene) amino] -5-fluorophenol (17.62 g, 100%). NMR (400 MHz, CDCl3) 6.83 (d, J = 10.2, 1H), 7.02 (m, 2H), 7.44 (m, 1H), 7.52 (m, 1H) , 8.85 (s, 1H). B. 8-bromo-1,7-difluorodibenzo [b, f] [1,4] oxazepine 24 ΕΡ 2 066 677 / ΡΤ

A preparation analogous to Example 5, step d, from 4-bromo-2 - [(2,6-difluorobenzylidene) amino] -5-fluorophenol (53.4 mmol) and CS2 CO3 (26 g, 80 mmol) The title compound (16.1 g, 97%). W. (±) - (cis) -7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2-d] ] [1,4] oxazepine-1-carboxylic acid

A preparation analogous to Example 5, step e, from 8-bromo-1,7-difluorodibenzo [b, f] [1,4] oxazepine (8 g, 25.8 mmol) and glutaric anhydride (5.9 g , 51.6 mmol). After cooling, the reaction mixture was dissolved in ethyl acetate, washed with water, dried (Na2 SO4) and evaporated to give the title carboxylic acid (10.9 g, 100%). d. (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl) carbamate

A preparation analogous to Example 5, step f, from (±) - (cis) -7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H- dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-carboxylic acid (10.94 g, 25.8 mmol), triethylamine (6.4 mL, 45.6 mmol), DPPA (7.2 mL, 33.31 mmol) and methanol (29 mL). The crude compound was purified by flash chromatography (SiO2, toluene: ethyl acetate = 6: 4) to give (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4- 14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (11 g, 94%). and. (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 4] oxazepin-1-yl) carbamate

A preparation analogous to Example 5, step g, from (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H- (11 g, 24 mmol), borane (1.0 M in THF, 24.2 g) in dichloromethane mL, 24.2 mmol) provided the crude title compound (10.5 g, 100%). 25 ΕΡ 2 066 677 / ΡΤ f. (±) - (cis) -7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4 ] oxazepine-1-amine

A preparation analogous to Example 5, step h, from (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (1.9 g, 4.3 mmol), acetic acid (9 mL) and hydrobromic acid (48%, 5 mL) gave the crude title compound (1.44 g, 88%). g. (±) - (cis) -7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepine-1-amine (4S) -2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide (1: 1)

A preparation analogous to Example 5, step i, was prepared from 2.2 g (5.77 mmol) of (±) - (cis) - (7-bromo-8,14-difluoro-1,3,4,14b tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-amine, 0.7 g (2.88 mmol) Recrystallization gave the title compound (0.8 g, 27%). (-) - (cis) -7-bromo-2-methyl- -8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-amine

A preparation analogous to Example 5, step j, from the salt of phenrenfos obtained in the previous step (1.33 g, 2.13 mmol) provided the title compound (0.8 g, 99%). and is. = 99.7%, (chiralpak AD-H 25 * 0.46 cm, heptane: 2-propanol = 8: 2). i. (-) - (cis) -N- (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) acetamide To a solution of (-) - (cis) -7-bromo-8,14-difluoro-1,3,4- Tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-amine in a mixture of CH2 Cl2 (10 mL) and triethylamine (0.44 mL, , 15 mmol) was added acetyl chloride (0.187 mL, 2.62 mmol) in CH 2 Cl 2 (5 mL) and stirred at room temperature for 1 h. A saturated aqueous NaHCO 3 solution was added and the organic layers were washed with brine, dried (Na 2 SO 4) and concentrated under reduced pressure to give the crude compound which was used without further purification (0.44 g, 100%). 26 ΕΡ 2 066 677 / ΡΤ j. (-) - (cis) -α- (7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) acetamide

A preparation analogous to Example 5, step 1, from (-) - (cis) -N- (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [ b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) acetamide (0.46 g, 1.08 mmol), CuCN (0.246 g, 2.71 mmol) and CuI (0.024 gave the crude which was purified by flash chromatography (SiO 2, CH 2 Cl 2 / ethyl acetate) to give the title compound (-) - (cis) -N- (7-cyano-8,14- tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) acetamide (0.277 g, 69% ). 1H NMR (400 MHz, DMSO), 1.50 (s, 3H), 1.54-1.75 (m, 3H), 1.95 (m, 1H), 3.15 (m, 1H), J = 10.6, 1H), 4.40 (m, 1H), 7.02 (m, 1H), 7.09 (d, J = 8.6, 1H), 7.31 (m, 1H), 7.44 (d, J = 10.2, 1H), 7.57 (d, J = 7.0, 1H), 7.75 ( d, J = 9.4, 1H). 19 F NMR (400 MHz, DMSO) -119, -113. (m / z) = 370 (M + H) +. k. (-) - (cis) -N- (7-cyano-6-chloro-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2 -d] [1,4] oxazepin-1-yl) -acetamide

A preparation analogous to Example 3 was prepared from (-) - (cis) -N- (7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) acetamide (0.277 g, 0.75 mmol) and NCS (0.10 g, 0.75 mmol). The crude compound was purified by HPLC to give the title compound (0.19 g, 62%). NMR (600 MHz, DMSO) 1.46-1.57 (m, 4H), 1.64 (m, 1H), 1.72 (m, 1H), 1.92 (m, 1H) (M, 1H), 4.31 (m, 1H), 7.05 (m, 1H), 7.05 (m, 1H) , 7.63 (m, 1H), 7.64 (d, J = 9.8, 1H), 7.81 (broad d, J = 9.8 , 1H). and is. = 100%, Rf = 17.8 minutes (chiralpak OD-H 25 * 0.46 cm, heptane: ethanol = 9: 1). (MIM) = 403.

[a] d 20 = -207 ° (c = 1.0025, THF). 27 ΕΡ 2 066 677 / ΡΤ

Example 7

Preparation of (-) - (eis) -N- (7-cyano-6-chloro-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1 , 2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = Cl, R3 = F, R4 = R5 = H) a. 2 - [[(5-bromo-2,4-difluorophenyl) imino] methyl] -6-fluorophenol

A preparation analogous to Example 5, step c, from 5-bromo-2,4-difluoroaniline (12.2 g, 58.57 mmol) and 3-fluoro-2-hydroxybenzaldehyde (8.2 g, 58.57 mmole) gave the title compound (19.3 g, 100%). B. 8-bromo-4,7-difluorodibenzo [gt; f] [1,4] oxazepine

A preparation analogous to Example 5, step d, from 2 - [(5-bromo-2,4-difluorophenyl) iminomethyl] -6-fluorophenol (58.57 mmol) and Cs2CO3 (29 g, 89 mmol) The title compound (16.6 g, 91%) was obtained. W. (Â ±) - (eis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepine-1-carboxylic acid

A preparation analogous to Example 5, step e, from 8-bromo-4,7-difluoro-dibenzo [b, f] [1,4] oxazepine (16.6 g, 53.54 mmol) and glutaric anhydride ( 9.15 g, 80.3 mmol) provided the title compound (13 g, 57%). d. (±) - (cis) - (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl) carbamate

A preparation analogous to Example 5, step f, was prepared from (±) - (cis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H- dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-carboxylic acid (13 g, 30.66 mmol), triethylamine (7.5 mL, 53 mmol), DPPA mL, 30.66 mmol) and methanol (32 mL) provided the crude compound (13.9 g, 100%). 28 ΕΡ 2 066 677 / ΡΤ e. (±) - (cis) - (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] oxazepin-1-yl) carbamate

A preparation analogous to Example 5, step g, from (±) - (cis) - (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-4-oxo-2H- dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (30.66 mmol), borane (1.0 M in THF, 31 mL, 31 mmol) gave the crude title compound (13.4 g, 100%). f. (±) - (cis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepine-1-amine

A preparation analogous to Example 5, step h, from (Â ±) - (cis) - (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) carbamate (30.66 mmol), acetic acid (50 mL) and hydrobromic acid (48%, 30 mL) provided the title compound (11.68 g, 100%). g. (-) - (cis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepine-1-amine (4S) -2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide (1: 1)

A preparation analogous to Example 5, step i, from (±) - (cis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f ] pyrido [1,2-d] [1,4] oxazepine-1-amine (30.5 mmol) and (+) - phenols (3.7 g, 15.29 mmol) in CH2 Cl2 (160 mL) ethanol (100 mL). Recrystallization gave the title compound (2.55 g, 17%). H. (-) - (cis) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] [1,4] ] oxazepine-1-amine

A preparation analogous to Example 5, step j, from the salt of phenrenfos obtained in the previous step (2.55 g, 4.1 mmol) gave the title compound (1.51 g, 97%). and is. = 99.8% (chiralpak AD-H 25 * 0.46 cm, heptane: ethanol = 8: 2). i. (-) - (cis) -N- (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, b] pyrido [1,2- d] 1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

ΕΡ 2 066 6 77 / EN

A preparation analogous to Example 5, step k, from (-) - (cls) -7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f ] pyrido [1,2-d] [1,4] oxazepine-1-amine (1.51 g, 4.0 mmol) provided the title compound (1.73 g, 91%). k. (-) - (cis) -N- (7-cyano-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

A preparation analogous to Example 5, step 1 from (-) - (cis) -N- (7-bromo-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [ b] furo [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (1.73 g, 3.63 mmol), CuCN (0.85 g, 9.0 mmol) and CuI (0.08 g, 0.36 mmol) provided the title compound (1.3 g, 82%). l. (-) - (cis) -N- (7-cyano-6-chloro-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- -d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

A preparation analogous to Example 3 from (-) - (cis) -N- (7-cyano-8,11-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [ 1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (1.3 g, 3.07 mmol) and NCS (0.42 g, 3.07 mmol ). The crude compound was purified by crystallization to give (-) - (cis) -N- (2H-7-cyano-6-chloro-8,11-difluoro-1,3,4,14b-tetrahydro- 2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2-trifluoroacetamide (0.57 g, 40%). NMR (400 MHz, CDCl3) 1.66 (m, 1H), 1.89-2.1 (m, 3H), 2.91 (m, 1H), 3.08 (m, 1H), 4. , 45 (m, 1H), 4.88 (m, 1H), 7.04-7.22 (m, 4H), 7.64 (broad, 1H). and is. = 100%, Rf = 22.9 minutes (chiralpak OJ-H 25 * 0.46 cm, heptane: ethanol = 9: 1). (MIM) = 457.

[a] d 20 = -196 ° (c = 1.01, THF).

Example 8

Preparation of (-) - (cis) -N- (7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d ] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = R3 = R4 = H, R5 = F) 30 ΕΡ 2 066 677 / ΡΤ a. (-) - (cis) -α- (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [d, f] pyrido [1,2- d] 4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

A preparation analogous to Example 5, step k, was prepared from 0.408 g (1.07 mmol) of (-) - (cis) -7-bromo-8,14-difluoro-1,3,4,14b- dihydro-2H-dibenzo [b, f] pyrido [1,2-d] [1,4] oxazepine-1-amine (Example 6, step h) gave the title compound (0.486 g, 95%). B. (-) - (cis) -N- (7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrido [1,2- d] 1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide

A preparation analogous to Example 5, step 1, from (-) - (cis) -N- (7-bromo-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [ b, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (0.486 g, 1.01 mmol), CuCN (0.23 g, 57 mmole) and CuI (0.022 g, 0.1 mmol) provided the title compound (0.397 g, 92%).

Melting temperature 262-263 ° C. NMR (600 MHz, DMSO) 1.59-1.65 (m, 2H), 1.91-2.03 (m, 2H), 3.60 (m, 1H), 3.93 (d, J = 14.5, 1H), 4.40 (d, J = 11, 1H), 4.51 (m, 1H), 7.04 (m, 1H), 7.13 (d, J = 7, 1H), 7.35 (m, 1H), 7.48 (d, J = 10.4, 1H), 7.63 (d, J = 6.4, 1H), 9.36 (broad d , J = 11.0, 1H). and is. = 100%, Rf = 16.5 minutes (chiralpak AD-H 25 * 0.46 cm, heptane: 2-propanol = 9: 1). (MIM) = 423.

[Î ±] D20 = -224Â ° (c = 1.08, THF).

Example 9

Preparation of (-) - (cis) -N- (7-cyano-6-chloro-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [d, f] pyrido [1 , 2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoroacetamide (Formula I, R1 = CF3, R2 = Cl, R3 = R4 = H, R5 = F)

A preparation analogous to Example 3 from (-) - (cis) -N- (7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo [d, f] pyrido [1,2-d] [1,4] oxazepin-1-yl) -2,2,2-trifluoro-4-acetamide (0.245 g, 0.58 mmol) and NCS 08 g, 0.58 mmol). The crude compound was purified by HPLC to give the title compound (0.159 g, 60%). NMR (CDCl3): 1.55 (m, 1H), 1.73 (m, 1H), 1.88 (m, 1H), 2.00 (m, 1H), 3.29 (m, J = 14.5, 1H), 4.47 (m, 2H), 7.06 (m, 1H), 7.16 (d, J = 9.2, 1H), 7.68 (d, J = 10.4, 1H), 9.39 (br, 1H). and is. = 100%, Rf = 5.9 minutes (chiralpak AD-H 25 * 0.46 cm, heptane: ethanol = 9: 1). (MIM) = 457.

[α] D 20 = -198 ° (C = 1.0075, THF).

Example 10

In vivo activity in rats

Inhibition of ovulation was studied following oral administration of the compounds of the invention in mature, cyclic rats. The animals were treated with a test compound (oral administration) over a complete cycle (4 days, from estrus to proestrus) and the number of eggs in the oviduct was evaluated microscopically by autopsy on the following (expected) estrus morning, . The mean number of eggs per mouse was calculated; the minimum active dose (MAD) was defined as the level at which the mean number of eggs was reduced by 60% compared to placebo treated animals.

As is evident from Table 1, the compounds of the present invention have a much higher in vivo activity. Unexpectedly and surprisingly, the particular combination of the 7-cyano and 8-fluoro substituents produces a higher activity profile than compounds related to a minimal difference in substitution pattern, such as 7-cyano but no 8 , or with an 8-fluoro substituent but without a cyano substituent at the 7-position, or those combining a cyano substituent and a fluoro substituent at positions other than 7 and 8. 32 ΕΡ 2 066 677 / ΡΤ

Table 1: In vivo progestagenic activity (inhibition of ovulation in a mouse) of compounds of the present invention with 7-cyano-8-fluoro and comparable compounds with different substitution patterns Number of Example MAD Structure (mg / kg) Patent Example 47 WO 03/084963 The invention relates to a process for the preparation of the compound of Example 52 of WO 03/084963, which is incorporated herein by reference in its entirety. EXAMPLE 57 of WO 03/084963 describes a process for the preparation of a compound of the invention in which the compound of formula (I) (E-N-4) 4-Eutomer of Example 58 of WO 03/084963 O / N - (H-N '- N' Example No. WO 03/084963 'O / Nr-H \ 0> 4 33 ΕΡ 2 066 677 / ΡΤ Example Number MAD Structure (mg / kg) Example 60 of WO 03/084963 About 1 Eutomer of Example 63 of WO 03/084963 N-ΓΗ \ _H -C-CF · cerca about 4 Exemp EXAMPLE 3 Cy / X &quot; EXAMPLE 4 XIII &lt; RTI ID = 0.0 &gt; EXAMPLE 5 Example 6 1-Hydroxy-3-oxo-4-oxo-3-oxo-3-methyl- Example No. Structure MAD (mg / kg) EXAMPLE 7 F-NMR (DMSO-d6) Î'(ppm) EXAMPLE 8 EXAMPLE 8 N- [1-O-O-O-O-O-O-O- 9 F Cl / V-nF and ~ cf &gt; 0 <0.02

Lisbon, 2010-11-04

Claims (26)

A compound of (cis) -8-fluorodibenzo [b, f] pyrido [1,2-d] oxazepine-1-amine according to Formula I R3 Formula I wherein R 1 is (C 1 -C 4) alkyl, optionally substituted with one or more halogen atoms; and R2 is selected from the group consisting of H, halogen, (C1-C6) alkyl, and CN; and R 3, R 4 and R 5 are each independently H or F. A compound according to claim 1, wherein R 2 is H. A compound according to claim 1, wherein R 2 is Cl. A compound according to claim 1, wherein R 2 is CN. A compound according to claims 1-4, wherein R 3 is H, R 4 is H and R 5 is H. A compound according to claims 1-4, wherein R 3 is F, and R 4 and R 5 are H. A compound according to claims 1-4, wherein R 4 is F, and R 3 and R 5 are H. A compound according to claims 1-4, characterized in that R 5 is F, and R 3 and R 4 are H. ΕΡ 2 066 677 / ΡΤ 2/3 A compound according to claims 1-8, wherein R 1 is CF 3. A compound according to claims 1-8, wherein R 1 is CH 3. A compound according to claim 1, wherein R 1 is CF 3 and each of R 2, R 3, R 4 and R 5 is H. A compound according to claim 1, wherein R 1 is CF 3, R 2 is Cl and each of R 3, R 4 and R 5 is H. A compound according to claim 1, wherein R 1 is CF 3, each of R 2, R 3, R 4 is H and R 5 is F. A compound according to claim 1, wherein R1 is CF3, R2 is Cl, both R3 and R4 are H, and R5 is F. A compound according to claims 1-14, which is levorotatory. A compound according to any of claims 1-15, for use in therapy. A contraceptive composition comprising a compound according to any of claims 1-15 and a contraceptively acceptable carrier. A pharmaceutical composition comprising a compound according to any of claims 1-15 and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 18 for hormone replacement therapy. A pharmaceutical composition according to claim 18 for the treatment of a gynecological disorder. Use of a compound according to any of claims 1-15 for the manufacture of a medicament. ΕΡ 2 066 677 / ΡΤ 3/3 Use of a compound according to any of claims 1-15 for the manufacture of a contraceptive. Use according to claim 21, wherein the medicament is for hormone replacement therapy or for the treatment of a gynecological disorder. 24. (eis) -8-Fluorodibenzo [b, f] pyrido [1,2-d] oxazepine-1-amine Compound according to Formula II Formula II wherein R 1 is (C 1 -C 4) alkyl, optionally substituted with one or more halogen atoms; and R2 is H; and R 3, R 4 and R 5 are each independently H or F. Use of a compound according to claim 25 for the production of a compound according to any one of claims 1-15. A process for producing a compound of Formula I by converting a compound of Formula II to a compound of Formula I through the use of CuCN, optionally in the presence of Cul. Lisbon, 2010-11-04